Autism Spectrum Disorders (ASD) and Schizophrenia are poorly understood because of the lack of good model systems. Genetic variation studies on patients have demonstrated increased or reduced copies of small chromosomal regions containing up to 50 or more genes. To study the impact of these copy number variations (CNVs) requires access to patient neurons. The discovery that skin fibroblasts can be reprogrammed into stem cells provides a novel system to produce neurons to study these disorders. These induced Pluripotent Stem (iPS) cells are produced by transfer of 4 genes into fibroblasts. Our long term goals are: 1) to determine whether the iPS cell system can identify differences in neuron function in human ASD and Schizophrenia patients, and 2) develop new chemical methods to generate human iPS cells with reduced or no genetic modifications. In the exploratory phase, iPS cell lines will be made from ASD and Schizophrenia subjects and parent controls. Our patients have known de novo CNVs that cover candidate genes involved in neurotransmission. Standard retrovirus delivery of 4 genes will be coupled with a novel EOS lentivirus that reports pluripotency and enhances isolation of human iPS cell lines. The iPS cell lines will be validated by differentiation into neurons and many cell types consistent with pluripotency, and the presence of the specific CNV confirmed. At the same time, the EOS lentivirus will be used to establish a novel high throughput assay using EGFP expression as an indicator of human iPS cell colonies. A pilot screen of a small chemical library will validate this assay and define novel chemicals that enhance reprogramming in the presence of only 2 retrovirus delivered genes. In the development phase, the ASD and Schizophrenia iPS cells will be characterized. First, the genetic stability of the CNVs will be assessed in culture. Expression of candidate genes that influence glutamatergic transmission will be determined in neurons produced from the IPS cells. The neurons will also be tested for maturation and electrical transmission to identify reproducible differences compared to the controls. Second, improved iPS cells to model these disorders will be generated using the best available transient chemical or genetic techniques that replace or reduce the number of genes transferred and their pluripotency established. Finally, a high throughput screen for novel enhancers of reprogramming in the presence of one retrovirus delivered gene will be performed on the full library of 100,000 chemicals. Lead hits will be tested in combinations and by structure modifications to optimize transient reprogramming of human cells. Overall, our iPS cell models of mental health disorders will correlate expression of candidate genes with neuronal function, and improved chemical reprogramming methods will be defined for this purpose. PUBLIC HEALTH RELEVANCE: New cell models of human Autism and Schizophrenia are relevant to public mental health by identifying how nerve cell function differs from normal. These cells will be used to safely test new treatments in the future. Development of improved methods to make the cell models will make this approach more broadly available, and may allow the cells to be used in transplantation therapies.